Structure Function Analysis of Staphylococcal Complement Inhibitors

葡萄球菌补体抑制剂的结构功能分析

• 批准号: 7382408
• 负责人: Brian V Geisbrecht
• 金额: $ 31.88万
• 依托单位: UNIVERSITY OF MISSOURI KANSAS CITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7382408
• 关键词: Active Sites; Address; Anti-Bacterial Agents; Appendix; Attenuated; Autoimmune Process; Bacterial Proteins; Binding; Binding Proteins; Binding Sites; Cardiovascular system; Catheters; Cells; Clinical; Community-Acquired Infections; Complement; Complement 3; Complement 3d; Complement Activation; Complement Factor H; Complement Inactivators; Complex; Condition; Disease; Endocarditis; Exposure to; Family; Fibrinogen; Funding; Genomics; Health; Helix (Snails); Homologous Gene; Homologous Protein; Human; Immune response; Immune system; Immunosuppressive Agents; Implant; Infection; Knowledge; Link; Longitudinal Studies; Masks; Measures; Mediating; Medical Device; Molecular; Molecular Conformation; N-terminal; Natural Immunity; Nature; Organism; Pacemakers; Physiological; Proteins; Pump; Reporting; Role; Septicemia; Series; Staphylococcus aureus; Structure; Structure-Activity Relationship; Surface Plasmon Resonance; System; Testing; Therapeutic; Virulence Factors; Work; activation product; base; biomaterial incompatibility; design; ear helix; extracellular; inhibitor/antagonist; insight; novel; pathogen; protein function; protein structure function; response; success

DESCRIPTION (provided by applicant): Staphylococcus aureus is a widespread, persistent human pathogen that has a long-standing and increasingly negative impact on human health. It is a leading cause of nosocomial and community-acquired infections, including several potentially fatal conditions of the circulatory system such as endocarditis and septicemia, as well as infections associated with implanted medical devices, such as intravascular catheters, pacemakers, and delivery pumps. Recent studies have demonstrated that S. aureus expresses several proteins that inhibit the innate and adaptive components of the human immune system and a body of evidence suggests that these proteins are critical to the success of S. aureus as a pathogen. While proper function of the complement system is essential for an efficient immune response against S. aureus, this organism has achieved several powerful and sophisticated mechanisms to attenuate complement function. Together with a newly identified homolog denoted Ehp, the Extracellular Fibrinogen-binding Protein (Efb) defines a novel family of complement inhibitory proteins that disrupt downstream functions of innate immunity by forming a potent complex with the native, unprocessed form of human complement component 3 (C3). However, a detailed understanding of the structure and mechanism of function for these proteins in the immunosuppressive repertoire of this ever more dangerous pathogen is lacking. To address this need during the requested funding period, we propose the following Specific Aims: 1. To Study the Structure/ Function Relationships of the Efb/C3 Complex 2. To Characterize the Structure, Dynamics, and Functions of the Ehp/C3 Complex 3. To Investigate the Structural Basis and Associated functions of Efb and Ehp-mediated Enhancement of Factor H Binding to C3 4. To Investigate the Molecular Basis and Functions of Efb Binding to Fibrinogen By studying the structure and function of these proteins, we will further our understanding of the mechanisms used by S. aureus to evade the immune system. In turn, this will promote our knowledge of the structure and mechanism of C3 recognition and inhibition during pathological situations. In the long term, these studies will provide important insights into the clinical promise for (a) antibacterial preventative measures that are designed to block the functions of immunosuppressive virulence factors from S. aureus, and (b) molecules which mimic their activities by blocking pathological overactivation of the complement system, as is seen in autoimmune and bioincompatibility disorders. Project Narrative: Structure/Function Analysis of Staphylococcal Complement Inhibitors Staphylococcus aureus is a widespread, persistent human pathogen that expresses several proteins that inhibit components of the human immune system. Among these, the Efb-family of secreted proteins has been shown to disrupt downstream function of complement response by binding and inactivating complement component C3. In this work, we propose to study the structure and function of these proteins and their complexes with C3. The results attained will further our understanding of the structure and mechanism of C3 recognition and inhibition of C3 during pathological situations. In addition, study of these S. aureus proteins should provide important insights into the clinical promise for therapeutics that either disrupt or mimic their function.

描述（由申请人提供）：金黄色葡萄球菌是一种广泛的，持续的人类病原体，对人类健康产生了长期且日益严重的负面影响。它是医院和社区获得性感染的主要原因，包括循环系统的几种潜在致命状况，例如心内膜炎和败血病，以及与植入的医疗装置相关的感染，例如血管内导管，起搏器和输送泵。最近的研究表明，金黄色葡萄球菌表达了几种蛋白质，这些蛋白质抑制了人类免疫系统的先天和适应性成分，并且有大量证据表明，这些蛋白质对于金黄色葡萄球菌作为病原体的成功至关重要。虽然补体系统的适当功能对于对金黄色葡萄球菌的有效免疫反应至关重要，但该生物已经达到了几种强大而复杂的机制来衰减补体功能。再加上新鉴定的同源性EHP，细胞外纤维蛋白原结合蛋白（EFB）定义了一个新型的补体抑制蛋白家族，该家族通过与天然，无人程序的人类补体组件3（C3）形成有效的复合物，破坏了先天免疫的下游功能（C3）。但是，缺乏对这些蛋白质的功能的结构和机制的详细理解，这些蛋白质在这种更危险的病原体的免疫抑制曲目中缺乏。要在请求的资金期内满足这一需求，我们提出以下具体目的：1。研究EFB/C3复合体的结构/功能关系2。以表征EHP/C3复合体的结构，动力学和功能3。研究EFB和EHP介导的h.与C3 4的结合功能的结构基础和相关功能，以研究C3 4。通过研究这些蛋白质的结构和功能，我们将进一步了解金黄色葡萄球菌逃避免疫系统的机制。反过来，这将促进我们对病理情况下C3识别和抑制的结构和机制的了解。从长远来看，这些研究将提供对（a）抗菌预防措施的临床承诺的重要见解，旨在阻止金黄色葡萄球菌的免疫抑制性毒力因子的功能，以及（b）分子，这些分子通过在自动化和生物含量的自动化性和生物膜上可以看出，通过阻止补体系统的病理过度活化来模仿其活动。项目叙述：葡萄球菌补体抑制剂金黄色葡萄球菌的结构/功能分析是一种广泛的，持续的人类病原体，表达了几种抑制人类免疫系统成分的蛋白质。其中，已证明分泌蛋白的EFB家庭通过结合和灭活补体成分C3破坏了补体反应的下游功能。在这项工作中，我们建议研究这些蛋白质及其与C3的复合物的结构和功能。所达到的结果将进一步理解病理情况下C3识别和抑制C3的结构和机制。此外，对这些金黄色葡萄球菌蛋白的研究应提供有关破坏或模仿其功能的治疗剂的临床希望的重要见解。